Piperine, an alkaloid naturally occuring in plants from family Piperacea, was found to enhance the absorption and/or bioavailability of nutrients1-3 and drugs.4-7 In a related prior art reference (Atal, C. K. et al. Indian J Exp Biol; 15 (December 1977): 1230-1232), synthetic derivatives of piperine were shown to exhibit synergism in larvacidal (killing larvae of houseflies) activity when combined with pyrethrin. Pyrethrin is a plant derived compound used as a bug-repellant. The various compounds tested by Atal, C. K. et al. were piperidine amides of tetrahydropiperic acid. Totally, 24 amides and 7 esters of tetrahydropiperic acid were prepared. Curcuma longa (Linn. Vern.: turmeric), Boswellia serrata (Roxb. Vern.: frankincense) and closely related Commiphora mukul (Hook, Vern.: gum-guggul) have been traditionally used in traditional Indo-Tibetan medicine as NSAIDs and in anti-neoplastic therapy.
Curcumin, demethoxycurcumin and bisdemethoxycurcumin (diferuloylmethane derivatives also referred to as curcuminoids), the naturally occurring yellow pigments in turmeric, inhibit gastrointestinal tumorigenesis during initiation and promotion in the experimental models. Possible mechanism may involve inhibition of nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and production of proinflammatory prostaglandins. Topical application of curcuminoids inhibits benzo[a]pyrene (B[a]P)-mediated formation of DNA-B[a]P adducts in the epidermis. It also reduces 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced increases in skin inflammation, epidermal DNA synthesis, ornithine decarboxylase (ODC) mRNA level, ODC activity, hyperplasia, formation of c-Fos, and c-Jun proteins, hydrogen peroxide, and the oxidized DNA base 5-hydroxymethyl-2′-deoxyuridine (HmdU).
Four major triterpene boswellic acids derived from frankincense gum inhibited in vitro the synthesis of DNA, RNA and protein in human leukemia HL-60 cells in a dose dependent manner with IC50 values ranging from 0.6 to 7.1 microM.(see U.S. Ser. No. 09/302,510 filed Apr. 30, 1999, the disclosure of which is hereby incorporated by reference).
The ferulate derivatives isolated from gum guggl showed a significant cytotoxic activity towards MCF-7 (breast) and PC-3 (prostate) tumor cells. The IC50 in both cells were 14.3 mcg/ml (25 μm). The ferulate derivatives decreased cell viability with IC50<25 μm in both transfected (P388/MDR) and parental cell lines. This finding suggests that these compounds might be able to overcome P-glycoprotein mediated drug resistance. (see U.S. Ser. No. 60/205,466 filed May 19, 2000, the disclosure of which is hereby incorporated by reference).
The above mentioned anti-cancer therapies have limitations in efficacy due to poor gastrointestinal absorption and/or insufficient tissue bioavailability of the compounds. The invention relates to of a compound developed from a natural alkaloid, piperine. The natural alkaloid, piperine, has been previously evaluated in oral dosages for its potential to enhance the gastrointestinal absorption of drugs and nutrients in animals and humans. Compounds successfully studied include drugs such as vasicine, pyrazinamide, rifampicin, isoniazid, propranolol, theophylline and phenytoin, and nutrients such as fat soluble beta-carotene, water soluble vitamin B6, vitamin C, coenzyme Q10 and the mineral selenium in the form of L-selenomethionine.